hnRNP H binding at the 5' splice site correlates with the pathological effect of two intronic mutations in the NF-1 and TSH  genes

Buratti, Emanuele; Baralle, Marco; Conti, Laura De; Baralle, Diana; Romano, Maurizio; Ayala, Youhna M.; Baralle, Francisco E.

doi:10.1093/nar/gkh752

Cited by 70 publications

(68 citation statements)

References 64 publications

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“…Mutations found in intronic sequences of TP splice sites in mitochondrial neurogastrointestinal encephalomyopathy patients lead to various exon skipping phenomena and consequent downregulation of TP activity. A similar case has been reported where a disease-causing substitution at the donor site of NF-1 exon 3 results in its skipping (60). Interestingly, exon recogni-tion in the mutant can be rescued by disruption of the binding of hnRNP H, which binds specifically to the donor sequence of NF-1 exon 3 and restricts the accessibility of U1 small nuclear ribonucleoprotein to the donor site.…”

Section: Discussionsupporting

confidence: 66%

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

Stark¹,

Bram²,

Akerman

et al. 2011

Journal of Biological Chemistry

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Thymidine phosphorylase (TP) catalyzes the conversion of thymidine to thymine and 2-deoxyribose-1-phosphate. The latter plays an important role in induction of angiogenesis. As such, many human malignancies exhibit TP overexpression that correlates with increased microvessel density, formation of aggressive tumors, and dismal prognosis. Because TP is frequently overexpressed in cancer, pro-drugs were developed that utilize TP activity for their bioactivation to cytotoxic drugs. In this respect, TP is indispensable for the pharmacologic activity of the chemotherapeutic drug capecitabine, as it converts its intermediary metabolite 5-deoxyfluorouridine to 5-fluorouracil. Thus, loss of TP function confers resistance to the prodrug capecitabine, currently used for the treatment of metastatic colorectal cancer and breast cancer. However, drug resistance phenomena may frequently emerge that compromise the pharmacologic activity of capecitabine. Deciphering the molecular mechanisms underlying resistance to TP-activated prodrugs is an important goal toward the overcoming of such drug resistance phenomena. Here, we discovered that lack of TP protein in drug-resistant tumor cells is due to unsplicing of its pre-mRNA. Advanced bioinformatics identified the family of heterogeneous nuclear ribonucleoproteins (hnRNP) H/F as candidate splicing factors potentially responsible for impaired TP splicing. Indeed, whereas parental cells lacked nuclear localization of hnRNPs H1/H2 and F, drug-resistant cells harbored marked levels of these splicing factors. Nuclear RNA immunoprecipitation experiments established a strong binding of hnRNP H1/H2 to TP pre-mRNA, hence implicating them in TP splicing. Moreover, introduction of hnRNP H2 into drug-sensitive parental cells recapitulated aberrant TP splicing and 5-deoxyfluorouridine resistance. Thus, this is the first study identifying altered function of hnRNP H1/H2 in tumor cells as a novel determinant of aberrant TP splicing thereby resulting in acquired chemoresistance to TP-activated fluoropyrimidine anticancer drugs.

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Section: Discussionsupporting

confidence: 66%

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

Stark¹,

Bram²,

Akerman

et al. 2011

Journal of Biological Chemistry

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“…HnRNPs are molecular determinants of all facets of mRNA processing including alternative splicing (66). Other HnRNPs have been shown to associate with ER␣, but this study is the first to report an interaction between ER␤ and HnRNP H (66,67). In this report the ER␤-HnRNP H interaction was enhanced by E2 in young animals but was decreased or unchanged by E2 in aged animals, suggesting that in aged animals the influence of E2 over the actions of an ER␤-HnRNP H complex might be altered.…”

Section: Discussionmentioning

confidence: 70%

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Mott

Pinceti

Rao

et al. 2014

Molecular & Cellular Proteomics

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Recent clinical evidence suggests that the neuroprotective and beneficial effects of hormone therapy may be limited by factors related to age and reproductive status. The patient's age and length of time without circulating ovarian hormones are likely to be key factors in the specific neurological outcomes of hormone therapy. However, the mechanisms underlying age-related changes in hormone efficacy have not been determined. We hypothesized that there are intrinsic changes in estrogen receptor ␤ (ER␤) function that determine its ability to mediate the actions of 17␤-estradiol (E2) in brain regions such as the ventral hippocampus. In this study, we identified and quantified a subset of ER␤ protein interactions in the ventral hippocampus that were significantly altered by E2 replacement in young and aged animals, using two-dimensional differential gel electrophoresis coupled with liquid chromatography-electrospray ionization-tandem mass spectrometry. This study demonstrates quantitative changes in ER␤ protein-protein interactions with E2 replacement that are dependent upon age in the ventral hippocampus and how these changes could alter processes such as transcriptional regulation. Thus, our data provide evidence that changes in ER␤ protein interactions are a potential mechanism for age-related changes in E2 responsiveness in the brain after menopause. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.031559, 760-779, 2014.The neuroprotective and beneficial effects of estrogens in the brain have been reported for decades, yet recent evidence from clinical trials suggests that the benefits of estrogens in postmenopausal women might not outweigh the risks (1-3). Specifically, the risk of cardiovascular disease and invasive breast cancer was significantly increased in postmenopausal women given hormone therapy as part of the largest clinical trial performed to date (Women's Health Initiative). These results sharply contradicted substantial evidence from numerous studies in animal models, prompting a reevaluation of the data from the Women's Health Initiative studies. Later it was determined that factors contributing to the observed detrimental effects of hormone therapy in the Women's Health Initiative study included advanced age, the types of synthetic estrogens and progestins used in the study, and, perhaps most important, the number of years postmenopause prior to the initiation of hormone therapy (4). However, more than 10 years after the conclusion of these studies there is little to no mechanistic explanation for how aging contributes to a change in estrogen signaling.One possibility is that there are age-related changes in the way the brain responds to estrogens. We hypothesized that there are intrinsic changes in the function of estrogen receptors in the brain with advanced age, and estrogen receptor ␤ (ER␤) 1 in particular has been shown to be a critical regulator of many neurobiological functions. An important component of ER␤ signaling is requisite associations with intracellular coregulatory proteins. ...

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“…shown to bind 5 0 splice sites in other genes and inhibit splicing [Romano et al, 2002;Buratti et al, 2004]. However, preliminary data predicting hnRNP H binding sites using information theory indicate that the cryptic site at 411 does not bind hnRNP H (Rogan, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Splice-site contribution in alternative splicing ofPLP1 andDM20: molecular studies in oligodendrocytes

et al. 2005

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Communicated by Mark H. PaalmanMutations in the proteolipid protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases PelizaeusMerzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G4A, c.453G4T, c.453G4C, c.45312T4C, c.45314A4G, c.347C4A, and c.453128 -1 46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS312T4C, IVS314A4G, C344A, and IVS3128-146del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing. Hum Mutat 27(1), [69][70][71][72][73][74][75][76][77] 2006.

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hnRNP H binding at the 5' splice site correlates with the pathological effect of two intronic mutations in the NF-1 and TSH genes

Cited by 70 publications

References 64 publications

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Splice-site contribution in alternative splicing ofPLP1 andDM20: molecular studies in oligodendrocytes

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